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ToxSci Advance Access published online on December 15, 2007
Toxicological Sciences, doi:10.1093/toxsci/kfm304
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© The Author 2007. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

A Gene-Shuffled Glyphosate Acetyltransferase Protein from Bacillus Licheniformis (GAT4601) Shows No Evidence of Allergenicity or Toxicity

Bryan Delaney*,1, John Zhang*, Gabrielle Carlson*, Jean Schmidt*, Barb Stagg*, Brad Comstock*, Amy Babb{dagger}, Carol Finlay{ddagger}, Robert F. Cressman§, Greg Ladics§, Amarin Cogburn§, Dan Siehl, Luda Bardina||, Hugh Sampson|| and Hanlll Youngshin|||

* Pioneer Hi-Bred International, Inc., Johnston, IA 50131 {dagger} Charles River Laboratories, Redfield, AR 72132 {ddagger} DuPont Haskell Laboratory, Newark, DE 19714 § DuPont Agriculture and Nutrition, Wilmington, DE 19880 Pioneer Hi-Bred International, Inc., Verdia Campus, Redwood City, CA 94063 || Department of Pediatrics and Immunobiology, Mount Sinai School of Medicine, New York, NY 10029 ||| Sungkyunkwan University School of Medicine, Seoul, Korea

1 To whom correspondence should be addressed at: Pioneer Hi-Bred International, Inc., 7250 NW 62nd Ave., P.O. Box 552, Johnston, IA 50131-0552, Phone: (515) 334-7086, Fax: (515) 334-4478, E-mail: bryan.delaney{at}pioneer.com

Received October 10, 2007; revision received December 4, 2007; accepted December 11, 2007


  Abstract

The glyphosate acetyltransferase (gat) gene from Bacillus licheniformis was subjected to multiple rounds of gene shuffling to optimize kinetics of corresponding GAT proteins to acetylate the herbicide active ingredient glyphosate. Genetically modified soybeans expressing the gat4601 gene (356043 soybeans) are tolerant to the application of glyphosate. The current manuscript reports the outcome of the allergenicity and toxicity assessment for the GAT4601 protein. Bioinformatic comparison of the amino acid sequence of GAT4601 did not identify similarities to known allergenic or toxic proteins. In vitro studies conducted with heterologously produced GAT4601 protein demonstrated that it was rapidly degraded in simulated gastric fluid containing pepsin (<30 sec) and in simulated intestinal fluid containing pancreatin (<2 min) and completely inactivated at temperatures above 56°C. The GAT4601 protein expressed in planta is not glycosylated and similar protein profiles were observed in flour extracts from 356043 soybeans and non-transgenic near isoline comparator soybeans (Jack) using serum from soy allergic persons. No evidence of adverse effects were observed in mice following acute oral exposure to 2000 mg/kg of GAT4601 protein or in a repeated dose dietary exposure study at doses of 800-1000 mg/kg/day. This comprehensive assessment demonstrates that the GAT4601 protein does not present a risk for adverse effects in humans when used in the context of agricultural biotechnology.

Key Words: Glyphosate acetyltransferase; Bioinformatics; In vitro digestibility; Allergenicity; Toxicology; Transgenic crop; Gene shuffling.


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